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MINI REVIEW
Year : 2012  |  Volume : 16  |  Issue : 8  |  Page : 176-177

Sub-clinical Addison's disease


Consultant Endocrinologist, Excel Center (a unit of Excecare Hospitals), Guwahati, Assam, India

Date of Web Publication4-Jan-2013

Correspondence Address:
Manash P Baruah
Consultant Endocrinologist, Excel Center (a unit of Excecare Hospitals), Guwahati, Assam - 781 007
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.104033

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   Abstract 

As autoimmune adrenalitis is fast replacing tuberculosis as the most common etiology cause of adrenal insufficiency, subtler forms of the same are being recognised as subclinical addison's disease. In this article, we review what is known about this entity till date.

Keywords: Subclinical addison′s, low dose synacthen test


How to cite this article:
Baruah MP. Sub-clinical Addison's disease. Indian J Endocr Metab 2012;16, Suppl S2:176-7

How to cite this URL:
Baruah MP. Sub-clinical Addison's disease. Indian J Endocr Metab [serial online] 2012 [cited 2020 Nov 26];16, Suppl S2:176-7. Available from: https://www.ijem.in/text.asp?2012/16/8/176/104033

As a clinical entity, Addison's disease has travelled far since the publication of the wonderful, precise, and accurate treatise by Thomas Joseph Addison. [1] During Addison's time, infection especially due to Mycobacterium tuberculosis was the main etiological factor, which has given way to auto-immune adrenalitis over last few decades. As regards our current understanding of etio-pathogenesis, there are three main categories, namely [A] adrenal dysgenesis/hypoplasia (e.g. congenital adrenal hypoplasia {AHC}, mutations of steroidogenic factor-1 {SF-1}, and ACTH unresponsiveness etc.), [B] impaired steroidogenesis (e.g. congenital adrenal hyperplasia {CAH}, mitochondrial disorders, the Smith-Lemli-Opitz syndrome {SMOS}, an enzyme deficiency in cholesterol metabolism etc.), and [C] adrenal destruction (e.g. autoimmune polyglandular syndrome (APS), adrenoleukodystrophy (ALD), adrenal hemorrhage, adrenal metastases, infections, and amyloidoses etc. Infection still continues to be an important factor in developing countries. [2]

The classical sub-clinical Addison's disease has been discussed in the background of autoimmune adrenalitis, which is characterized by presence of adrenal auto-antibodies and more often than not the occurrence of other autoimmune endocrinopathies. Although it may be a part of autoimmune polyglandular syndrome (APS) I and II and IV conditions where involvement of many other hormonal deficiencies predate that of adrenal deficiency, its diagnosis may remain elusive because of difficulty in demonstrating it in the sub-clinical phase. [3] The natural history of Addison's disease can be divided into four distinct stages, each characterized by documentable biochemical changes, such as, stage 0: Normal adrenal function with normal plasma adrenocorticotropin (ACTH), basal and ACTH-stimulated cortisol, PRA, serum aldosterone, stage 1: Increase plasma renin activity (PRA) and normal or low serum aldosterone levels and appropriate response to ACTH, stage 2: Low cortisol response to ACTH, stage 3: Increase plasma ACTH, basal serum cortisol at lower end of normal, and absent cortisol response to ACTH, stage 4: Low serum or urinary cortisol along with highly elevated plasma adrenocorticotropin (ACTH) with evident features of adrenocortical failure. [4],[5] Stage 1-3 would fall into sub-clinical category, while stage 4 is by and large clinical. Stage 0 would include all those healthy individuals with higher risk of developing adrenal failure. In other words, they belong to so-called potential stage.[3] There is great variation in the time taken by different individuals in progressing from stage 0 to stage 4, i.e. potential to clinical stage. Documentation of adrenal auto-antibodies, which are present in high-risk individuals irrespective of the aforesaid stages, is useful in segregating high-risk individuals from normal population. Auto-antibodies against the steroidogenetic enzyme 21-hydroxylase (21OHAb) has been found to be most useful in early identification at risk individuals. [6] The accuracy of risk prediction can be improved by inclusion of genetic risk alleles in the calculation, for example, genes of human leukocytic antigen (HLA) region such as DR3-DQ2, DR4-DQ8, MICA. [7]

Stimulation of the adrenal cortex by synthetic ACTH (synacthen, 250 μgm) to demonstrate either absolute or delta rise in cortisol is a well-validated test to confirm both primary and secondary adrenal insufficiency. [8] However, due to supra-physiological stimulation, this test lack the sensitivity to screen sub-clinical Addison's disease successfully. Hence, a lower dose of ACTH has been proposed, with 1 μgm being studied most extensively. [9] However, others have claimed acceptable sensitivity even with dose of ACTH as low as 0.06 μgm. [8] There is increased acceptability of the low dose synacthen stimulation test (SST), specially for screening of patients for sub-clinical primary or secondary adrenal insufficiency. [10],[11]

Most of authors from the sub-continent working in this field have shown sub-clinical primary adrenal insufficiency during active phase of tubercular infection, [12],[13] which reverses when the infection is suppressed successfully with anti-tubercular chemotherapy. [14] Maximal reversal occurs following six months of chemotherapy and correlated well with cure of disease in most patients.

 
   References Top

1.Addison T. On the constitutional and local effects of disease of the supra-renal capsules. London: Highley, 1855.   Back to cited text no. 1
    
2.Ten S, New M, Maclaren N. Clinical review 130: Addison's Disease. J Clin Endocrinol Metabolism 2001;86:2909-22.   Back to cited text no. 2
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3.Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndrome: Autoantibodies, autoantigenes, and the applicability in diagnosis and disease prediction. Endocr Rev 2002;23:327-64.   Back to cited text no. 3
[PUBMED]    
4.Betterle C, Scalici C, Presotto F, Pedini B, Moro L, Rigon F, et al. The natural history of adrenal function in autoimmune patients with adrenal autoantibodies. J Endocrinol 1988;117:467-75.  Back to cited text no. 4
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5.Coco G, Pra CD, Presotto F, Albergoni MP, Cristina Canova C, Pedini B, et al. Estimated Risk for Developing Autoimmune Addison's Disease in Patients with Adrenal Cortex Autoantibodies. J Clin Endocrinol Metab 2006;91:1637-45.   Back to cited text no. 5
    
6.Betterle C, Volpato M, Rees Smith B, Furmaniak J, Chen S, Greggio NA, et al. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: Markers of low progression to clinical Addison's disease. J Clin Endocrinol Metab 1997;82:932-8.  Back to cited text no. 6
[PUBMED]    
7.Laureti S, De Bellis A, Muccitelli VI, Calcinaro F, Bizzarro A, Rossi R, et al. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison's disease. J Clin Endocrinol Metabol 1998;83:3507-11.   Back to cited text no. 7
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8.Husebye ES, Løvås K. Immunology of Addison's disease and premature ovarian failure. Endocrinol Metab Clin N Am 2009;38:389-405.  Back to cited text no. 8
    
9.Roberta Giordano R, Balbo M, Picu A, Bonelli L, Berardelli R, Falorni A. Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: Evidence for subclinical primary hypoadrenalism? Eur J Endocrinol 2006;155:421-8.   Back to cited text no. 9
    
10.Patel L, Clayton PE. Clinical usefulness of the low dose ACTH test. J Endocrinol Inv 1999;22:401-4.   Back to cited text no. 10
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11.Giordano R, Pellegrino M, Oleandri S, Baldi M, Balbo M, Laureti S, et al. Adrenal Sensitivity to Adrenocorticotropin 1-24 Is Reduced in Patients with Autoimmune Polyglandular Syndrome. J Clin Endocrinol Metab 2004;89:675-80.   Back to cited text no. 11
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12.Sarma GR, Immanuel C, Ramachandran G, Krishnamurthy PV, Kumaraswami V, Prabhakar R. Adrenocortical function in patients with pulmonary tuberculosis. Tubercle 1990;71:277-82.   Back to cited text no. 12
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13.Prasad GA, Sharma SK, Mohan A, Gupta N, Bajaj S, Saha PK, et al. Adrenocortical reserve and morphology in tuberculosis. Indian J Chest Dis Allied Sci 2000;42:83-93.   Back to cited text no. 13
[PUBMED]    
14.Sharma SK, Tandan SM, Saha PK, Gupta N, Kochupillai N, Misra NK. Reversal of subclinical adrenal insufficiency through antituberculosis treatment in TB patients: A longitudinal follow up. Indian J Med Res 2005;122:127-31.  Back to cited text no. 14
    




 

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